Title

Authors

Date of Completion

January 2009

Keywords

Psychology, Psychobiology

Degree

Ph.D.

Abstract

The prefrontal cortex plays an important role in working memory, or the ability to hold information "on-line" to make a proper response. The neurotransmitters dopamine and glutamate are critical for optimal prefrontal function. Schizophrenia is a neuropsychiatric disorder which is characterized by positive symptoms, including hallucinations and delusions; negative symptoms such as psychomotor depression, blunted affect and social withdrawal; and cognitive dysfunction including deficits in working memory. Among these symptoms, deficits in working memory and executive function are most highly correlated with patient outcome, and their abilities to maintain jobs and function normally in society; however, antipsychotics have had limited success in treating these deficits. The goals of this research were to develop a model of cognitive dysfunction with relevance to schizophrenia, and to provide a platform to test potential treatments for cognitive impairments. The model used in these studies was acute administration of subanesthetic ketamine in the nonhuman primate. Ketamine is an anesthetic commonly used in veterinary medicine, which blocks NMDA glutamate receptors. Ketamine produces behaviors reminiscent of positive- and negative-like symptoms, as well as profound impairments in working memory performance. Using this model, various targets were tested on working memory performance. Results revealed that acute pretreatment with the commonly prescribed antipsychotic, risperidone, was ineffective in the model; however, D1-type dopamine receptor agonists ameliorated ketamine-induced working memory deficits, suggesting that targeting the D1 receptor may be valuable in developing a treatment for cognitive dysfunction in schizophrenia. These cognitively enhancing effects with a D1 agonist were reversed following pretreatment with a selective D1 antagonist, suggesting that the cognitive effects of the D1 agonist were, indeed, selectively mediated by the D1 receptor. Finally, potentiating transmission at AMPA glutamate receptors reversed ketamine-induced working memory impairments similar to D1 agonist pretreatment, indicating that the AMPA receptor may be another viable target in the treatment of cognitive dysfunction. Results from this research suggest an acute ketamine model of cognitive dysfunction in the nonhuman primate may prove extremely valuable in screening novel targets for cognitive enhancement in schizophrenia. Furthermore, this research provides support for targeting both the D1 and AMPA receptors in treating cognitive dysfunction.^